Why Does Our Own Immune System Attack Us in COVID-19? What Is Cytokine Release Syndrome?

The novel coronavirus causes COVID-19 infection, which is mild in most people, although around 20% of patients require hospitalization. Interestingly, this virus, which humanity is encountering for the first time, causes an abnormal immune system response, particularly in older people and those with other illnesses. In other words, our immune system attacks our own body. New research shows that this can occur not only in older people with additional illnesses, but also in young adults. The cellular mechanism causing our immune system to turn against us is cytokine release syndrome.

- Related topic: What Is the Innate Immune System and How Does It Work? Its Critical Role in Coronavirus Infection

Around 15-20% of COVID-19 cases develop the challenging medical condition called acute respiratory distress syndrome (ARDS). This resembles conditions seen in cases of the earlier coronaviruses SARS and MERS, as well as in patients receiving the living medicine CAR-T (chimeric antigen receptor T cell) therapy for leukemia: ARDS associated with cytokine release syndrome and secondary hemophagocytic syndrome (hemophagocytic lymphohistiocytosis). In this context, treatment strategies targeting cytokine release syndrome (for example, tosilizumab, which blocks IL-6 receptors) have rapidly entered clinical trials for COVID-19.

The novel coronavirus begins entering our cells by binding to cell-surface angiotensin-converting enzyme 2 (ACE-2) receptors. A serine protease in the host cell (our cells), TMPRSS 2 (proteases are enzymes that break down proteins), then cuts the virus’s spike protein at a particular site. This allows the viral envelope to fuse, or merge, with the host cell membrane. Viral RNA thus enters the host cell.

The ACE-2 receptor is found in humans particularly in cardiopulmonary tissues (those related to the heart and lungs). It is also present on certain immune cells, such as monocytes and macrophages.

One of the most important findings in COVID-19 is a reduced lymphocyte count (lymphopenia), which has been associated clinically with disease severity. Previous studies have shown that SARS-CoV effectively infects human monocytes and dendritic cells, and that MERS-CoV infects monocytes and T cells. Excessive release of proinflammatory cytokines, particularly IL-6 (interleukin 6), correlates with the development of acute respiratory distress syndrome and other poor clinical outcomes. This correlation has also been found with C-reactive protein, whose release increases with IL-6.

Unknowns and Mysteries...

The novel coronavirus (SARS-CoV-2) also appears likely to infect dendritic cells. Early in viral infection, suppressing these cells, which are vital for activating the adaptive immune system, prevents immune cells responsible for recognizing and eliminating virus-infected cells, particularly cytotoxic T cells (CD8+) and NK (natural killer) cells, from becoming activated and performing their roles. Type-1 interferons also help identify and eliminate virus-infected cells in viral illnesses. The adaptive immune response is specific: it enables the elimination of virus-infected cells, while the innate immune system is nonspecific and generates more general responses. SARS-CoV-2 blocks specific immune responses at an early stage by breaking the bridges between our immune systems.

Explanation of the Infographic Below: Coronavirus infection activates monocytes, macrophages and dendritic cells. IL-6 release causes excessive activation of inflammatory pathways and differentiation of helper T cells into type 17 (T helper 17) through cis-signaling. Trans-signaling also activates inflammatory pathways in many cells, including endothelial cells. Increased cytokine production ultimately leads to severe COVID-19 with ARDS and hypotension. Drugs providing IL-6 antagonism (tosilizumab, sarilumab and siltuksimab) may be useful in managing ARDS.

Betacoronavirus infection of monocytes, macrophages and dendritic cells results in increased secretion of IL-6 and other inflammatory cytokines by these cells. Looking at the cellular signaling pathways of IL-6, we encounter two main pathways. The first is cis-signaling, or the classical pathway. In cis-signaling, IL-6 interacts with membrane-bound IL-6 receptors and, through Janus Kinases and the transcription factor STAT3, regulates gene expression in various ways in different immune cells. Membrane-bound IL-6 receptors are present on immune cells; their presence in other tissues is limited. The second pathway is trans-signaling. The difference here is that high concentrations of IL-6 bind to soluble IL-6 receptors circulating in our blood. This complex causes the effects of IL-6 to occur in every cell in our body, including the endothelial cells lining the inner walls of our blood vessels. These cells release vascular endothelial growth factor (VEGF), monocyte chemoattractant protein 1, IL-8 and even more IL-6, while expression of the E-cadherin protein on their surfaces decreases. This mechanism is how a systemic cytokine storm begins to develop. Increased VEGF and decreased E-cadherin expression increase vascular permeability, and blood inside the vessels begins leaking into the tissues. This fluid entering the tissues plays an important role in the pathophysiology of ARDS. It causes the lungs to become unable to perform their normal functions and blood pressure to fall.

Secondary hemophagocytic syndrome is a condition involving excessive systemic inflammation. It is characterized by excessive cytokine release, cytopenias (low blood and immune cell counts) and multiple organ failure. High serum ferritin levels are another prominent finding. The most common cause in adults is severe viral illness, and the syndrome can also occur in patients with leukemia receiving the living medicine CAR-T. Elevated ferritin levels indicate activated macrophages and their role in iron metabolism in the reticuloendothelial system. Increased serum ferritin levels were also found in a retrospective study of COVID 19 patients.

Cytokine release syndrome and secondary hemophagocytic syndrome can develop in patients receiving the living medicine CAR-T (chimeric antigen receptor T cell) therapy. Emily Whitehead, a child with B-cell acute lymphoblastic leukemia and the first patient in whom this treatment was tried in 2012, developed severe cytokine release syndrome and secondary hemophagocytic syndrome. Her condition progressed to multiple organ failure and did not respond to the standard treatment, corticosteroids. Because her serum IL-6 level was very high, Tosilizumab, an IL-6 receptor antagonist approved until then for rheumatic diseases, was tried. She received only a single dose of Tosilizumab on the seventh day after CAR-T therapy. Her condition began to improve within hours, ARDS regressed, and mechanical ventilator support was no longer needed. Tosilizumab has been approved by the FDA (US Food and Drug Administration) for cytokine release syndrome caused by CAR-T therapy. Its effectiveness has been demonstrated in hundreds of patients, with minimal adverse effects.

The success of IL-6 receptor antagonists in treating cytokine release syndrome and secondary hemophagocytic syndrome illustrates the importance of the IL-6 signaling pathway in cytokine-induced inflammatory conditions. Serum cytokine levels are also markedly elevated in severe COVID-19, and these patients may benefit from inhibition of the IL-6 signaling pathway. A study of 21 COVID-19 patients in China is promising. These patients showed reductions in fever and oxygen requirements from the first day of Tosilizumab treatment. Similar clinical trials continue worldwide.

Corticosteroids are often used to treat sepsis-related ARDS. However, in SARS and MERS patients, corticosteroids have been shown to have no effect on mortality and to delay clearance of the virus from the body (viral clearance). The consensus of the WHO and infectious disease specialists is therefore against using systemic corticosteroids to treat COVID-19 patients. Although the likelihood of complications with one or two doses of IL-6 antagonists is quite low, higher doses can cause complications such as fungal infections and jawbone necrosis.

First used to treat rheumatic diseases, tosilizumab was subsequently approved for excessive inflammation caused by CAR-T. Today, it is being evaluated in clinical trials involving COVID-19 patients. Treatments targeting IL-6 also seem quite likely to be used in future outbreaks caused by other viruses, such as influenza and Ebola. However, it should be remembered that the purpose of IL-6 receptor antagonism in COVID-19 management is to reduce the need for intensive care among patients with severe COVID-19. The main long-term goals for COVID-19 treatment should be the development of antiviral medicines and a vaccine.

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